Important News for the Parkinson’s Disease Community: More Evidence that Sinemet and Madopar are Not Toxic and do Not Accelerate Disease Progression

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration. http://mdc.mbi.ufl.edu

Many Parkinson’s disease patients and families members have been unnecessarily alarmed by the continuing reports that Sinemet and/or Madopar (European Sinemet) may accelerate disease progression, and that doses and drug intervals should be limited. These reports have unfortunately been fueled by sparse human evidence. Patients need to be aware that dopamine replacement therapies such as Sinemet and Madopar remain the single most effective, and single most important treatment for Parkinson’s disease worldwide. This month’s “What’s Hot” column will focus on the evidence including the most recent paper on this important topic.
In this month’s issue of Neurology, important evidence is presented that dopamine replacement therapy is not toxic, and does not accelerate disease progression. Parkkinen and colleagues at Queen Square in London examined pathology in 96 post-mortem Parkinson’s disease brains, and paired the tissue with clinical information including levodopa use. The study concluded that in the human condition “chronic use of L-dopa does not enhance progression of Parkinson’s pathology.”
In an accompanying editorial, two prominent neurologists in the field pointed out that there “remains lingering concerns as to whether levodopa is toxic to dopamine neurons and accelerates the degenerative process.” The science quoted to support these claims has included levodopa undergoing auto-oxidation, and forming reactive oxygen species and toxic protofibrils. Additionally, the science includes a classical experiment that showed when levodopa was mixed with brain cells placed in a dish, there was toxicity. The research, however, has fallen short in demonstrating toxicity of the drug in the human form of Parkinson’s disease. In fact, there now exists broad levels evidence from many studies across many countries (including most recently the ELLDOPA study) that levodopa is extremely beneficial to the human patient, and that levodopa has had a positive effect on disease course. Sinemet was recently reported as the most commonly administered drug among 4000+ patients being followed longitudinally in the National Parkinson Foundation Quality Improvement Initiative study. Expert practitioners who reported in this database, utilized levodopa more than any other drug-- including dopamine agonists, and they used levodopa more (not less) as disease durations increased.
What all this adds up to for patients and for Parkinson’s sufferers is that Sinemet and Madopar should be considered safe and effective as treatments for Parkinson’s disease. The doses and intervals should be frequently adjusted by an experienced neurologist/practitioner in order to maximize benefits, and to tailor to individual symptoms. Patients and families should keep in perspective that the “talk” about levodopa being toxic and accelerating disease progression can prove a major distractor to good care practices. Precious minutes in the doctor-patient relationship should not be wasted on these claims, and prescribers should not avoid or under-dose this critical therapy, especially in patients with treatable symptoms. Critics of Sinemet and Madopar will need to bring forward much stronger human data if they wish to change clinical practice. In the mean time, we need to serve our patients by sharing with them the weight of the evidence which strongly supports that levodopa replacement therapy is not toxic, and does not accelerate Parkinson’s disease.
Selected References:
Parkkinen L, O'Sullivan SS, Kuoppamäki M, Collins C, Kallis C, Holton JL, Williams DR, Revesz T, Lees AJ. Does levodopa accelerate the pathologic process in Parkinson disease brain? Neurology. 2011 Oct 11;77(15):1420-6. Epub 2011 Sep 14.
Warren Olanow C, Obeso JA. Levodopa toxicity and Parkinson disease: Still a need for equipoise. Neurology. 2011 Oct 11;77(15):1416-7. Epub 2011 Sep 14.
Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA. Arch Neurol. 1999 May;56(5):529-35.

Good article. I was under the mistaken impression when I first saw the brain doc and wanted to hold off on Sinemet. I was afraid I would "use up" my dopamine. It is good to see numerous sources debunking my original belief! Hopefully, all the newbies will be better informed than I was and not try to be macho and hold off on the critical meds.

Thank you for posting this! It is comforting to hear that l-dopa doesn't appear to worsen brain pathology, but what about phenotype? Am I correct in saying that phenotype/symptomatology does not seem to correlate well with objective studies like SPECT/PET scans? Can I therefore extend that thought to apply to brain biopsy? Or do we simply need more information?
Also, I think for many of us we try to keep the dose of levodopa low due to dyskinesias. Is that still advisable?

The first thing I want to say is thanks for sending the link to the article on Medscape, but I can't access it. Maybe you can post the authors, title, and the references and we can comment.

Second, the pathology article did correlate to clinical symptoms. There have also been other studies and none have clearly shown that taking levodopa is bad for accelerated disease progression.

The notion of under-dosing to avoid dyskinesia and other issues can be troublesome. If you encounter dyskinesia, you can adjust dose and interval, however if you under-dose on purpose you may be robbing yourself of benefit and quality of life. My advice is to get maximal symptom improvement without side effects, but I tell my patients not to under-dose. Get that blood level back to a therapeutic range. There has been too much made of purposely under-dosing without any good evidence to support that strategy! Take what you need, on time, every time.

The first thing I want to say is thanks for sending the link to the article on Medscape, but I can't access it. Maybe you can post the authors, title, and the references and we can comment.

I don't have a login to Medscape either, but strangely I can access the article when Googling "More Neuropathy in Levodopa-Treated Parkinson's Patients" and clicking on the exact same link, but not when clicking directly on the link from this page....

I copied the article below. Formatting is not great but this should give some information though

November 4, 2011 — New evidence suggests that clinical testing for neuropathy in patients with Parkinson's disease receiving long-term levodopa therapy may be advisable.

New findings show that neuropathy is more prevalent in 'patients with Parkinson's disease, and point to a potential link with vitamin B12 deficiency and cumulative levodopa exposure.

"The description of the increased prevalence of neuropathy in Parkinson's disease is recent and remains controversial," acknowledge the investigators led by Yusuf Rajabally, MD, from the University Hospitals of Leicester in the United Kingdom. "Precise underlying pathophysiologic mechanisms implicated also remain debated as are the etiologies and consequences of neuropathy in this population."

These new results support an increased neuropathy prevalence in Parkinson's and "suggest the practical value of measuring vitamin B12 levels in levodopa-treated patients with PD, for whom serial clinical assessments for neuropathy appear justified. Trials of prophylactic replacement therapy may now require consideration."

The results were published online November 2 in Neurology.

Is it conceivable that for 40 years we have overlooked an insidious long-term levodopa treatment adverse effect?

In an accompanying editorial, François Tison, MD, and Gwendal Le Masson, MD, from Bordeaux University in France, ask, "Is it conceivable that for 40 years we have overlooked an insidious long-term levodopa treatment adverse effect, such as neuropathy, in idiopathic Parkinson's disease?"

They say the role remains hypothetical, but "the clinical relevance is evident, as sensory neuropathy may contribute to impaired balance and neuropathic pain."

In this cross-sectional study of 37 patients with Parkinson's disease and 37 age- and sex-matched controls, investigators evaluated the prevalence of neuropathy using the Utah Early Neuropathy Scale, a sensitive and validated scale.

The odds ratio for neuropathy was 6.9, with a 95% confidence interval of 1.78 to 26.73.

Patients With Neuropathy

Outcome

Patients with Parkinson's, n (%)

Control Subjects, n (%)

P Value

Neuropathy

14 (37.

3 (8.1)

.005

Investigators found that vitamin B12 deficiency was a significantly more common cause of neuropathy (P = .024), and vitamin B12 levels were also significantly lower in patients with Parkinson's disease and neuropathy than in control patients with neuropathy and no Parkinson's (P =.002).

They also found that cumulative levodopa exposure correlated with Parkinson's duration (P =.001) and vitamin B12 levels (P =.044).

"In view of these data," the editorialists add, "we now need well-designed unselected population-based investigations and at best prospective epidemiologic studies, as well as experimental and clinical/electrophysiologic studies either demonstrating or refuting a direct causative link between levodopa exposure in idiopathic Parkinson's disease, neuropathy, and vitamin B12 deficiency or increased homocysteine and methylmalonic acid."

Meanwhile, what should be done for patients with Parkinson's disease?

The investigators call for clinical assessment of neuropathy in patients treated with levodopa on a long-term basis. They also recommend a classic workup including vitamin B12, homocysteine, methylmalonic acid levels in patients with confirmed neuropathy.

This study was funded by the Leicestershire Neurological Trust, a Registered Charitable Organization in the United Kingdom. Dr. Yusuf Rajabally received an educational grant, unrelated to this study, from UCB. Jean Martey, BSc, received a grant from GlaxoSmithKline and speaker honoraria from Abbott and UCB.

Thank you for this information. Whether levodopa causes a neuropathy is an unrelated issue. The levodopa toxicity argument is based on whether it accelerates disease progression. Any drug can have a specific side effect like neuropathy. The findings of that study are controversial, however if on levodopa and you develop numb feet you should have a neuropathy workup. If it is B12 deficiency it is a snap to treat with shots and pills and you can also stay on levodopa.

Thank you for this information. Whether levodopa causes a neuropathy is an unrelated issue. The levodopa toxicity argument is based on whether it accelerates disease progression. Any drug can have a specific side effect like neuropathy. The findings of that study are controversial, however if on levodopa and you develop numb feet you should have a neuropathy workup. If it is B12 deficiency it is a snap to treat with shots and pills and you can also stay on levodopa.

Yes, it is unrelated to disease progression and toxicity on dopamine cells. But it is raising question about possible toxicity of levodopa on other cells.

The argument in the paper is weak and consequences look treatable.

But my question was about how much this impact the decision to delay the start of levodopa treatments. Combined with the case for starting with a dopamine agonist to lower risks of later dyskenisia, this is possibly one other element to consider.

We agree this isn't an all or nothing answer. Confirmations of the ELLDOPA study findings are very important in asserting the benefits of using levodopa. But I'd be interested in getting a finer grain understanding of what is the optimal strategy concerning the start of levodopa treatment

In my mind for my patients I can tell you what I do. I tailor a therapy to completely control symptoms and I see them frequently to change doses, intervals and drugs as the disease progresses. If they tolerate an agonist without side effects, then I am happy to offer. I am just as happy to start or add or substitute levodopa, but I will not purposely under-dose. The plan is to optimize medications and watch the patient carefully and adjust as needed. Agonists are less potent (less bang) so of course have less dyskinesia. Remember if you get dyskinesia then adjustments in dose and interval and discussions of other therapies should follow.

Hi Dr. Okun,
I just wanted to respond to a few of your points on this thread. First of all, judging from following quote which is directly from the ELLDOPA study, it sure sounds to me like it was inconclusive:

"The question of whether levodopa has a protective or toxic effect in Parkinson's disease… cannot be answered with certainty, and future studies will be needed."
N Engl JMed 2004;351:2498-2508

secondly, what are your thoughts on the STRIDE-PD study? This was the study that was hoping to demonstrate that levodopa/carbidopa/entacapone (LCE) would delay the onset of dyskinesia as compared to levodopa/carbidopa (LC).

However, what they found was that LCE actually resulted in shorter duration to onset of dyskinesia, as well as higher incidence. Here are some statistics from the study.

The mean number of weeks to onset of dyskinesia among LCE group was 74.2 and 79.1 weeks in the LC group.

That's only a year and half, in either group.

By week 134, 34.3% in the LCE and 27.7% in the LC group were experiencing dyskinesia..

Just looking at the LC group, certain subgroups were especially susceptible to developing dyskinesia, including those under 65 (37.5%); women (30.7%); and those weighing less than 75 kg (40.9%.).

But then if you look at the LCE group, the same subgroups were even more susceptible to dyskinesia: those under 65 (45.7%); women (42.2%); those weighing less than 75 kg (43%).

And ringing in at the highest percent of all in the LCE group, those with disease duration of less than two years (47.8%).

And finally, the authors conclude, as have many before them, that a higher levodopa dose was significantly associated with development of dyskinesia:

"Further, higher doses of L-dopa in both LC and LCE groups were associated with increased dyskinesias 26.4% of 375 patients receiving less than or equal to 400mg/day of L-dopa compared with 45.4% of 370 patients receiving greater than equal to 400mg/day""

I'd also like to ask what the success rate is in reversing dyskinesia once it starts. And by reversing I don't mean temporarily alleviating, I mean eradicating.

I'd also like to ask how long the average person with Parkinson's lives with the disease. I'm thinking that if average age of diagnosis is 65, and average life expectancy in this country 79, even if Parkinson's shortens one's lifespan by a couple of years, that's a good 10+ years with the disease – and what about the folks diagnosed under 50 or under 40 even? If dyskinesia can be expected to begin within two years, what does life look like at year eight or nine, or 20 or 25?

And finally, I'd like to suggest that the definition of toxic is broader than "accelerates disease progression." For example, I'd like to suggest that dyskinesia is evidence of toxicity – what are your thoughts on that idea?

You have a lot of insightful questions and comments in your post, and none have distinct answers. I will post so others can read and comment.

I agree that toxic and accelerating disease progression could be considered more broadly.

The Sydney Natural History PD study showed life expectancies were quite variable and in the range of 10-15 years, but we have a project at NPF following lots of people in our centers with PD over 20 years, and some over 30. PD is not one disease.

Levodopa given to PD patients results in motor fluctuations and dyskinesia in 50% by 5 years. It can be addressed by lowing doses and changing frequencies-- also by using other meds, duodopa, and DBS-- there is no specific answer to your question on response rates because it is variable among sufferers.

Hope that helps a little.

The Stride-PD really did show that Comtan in Stalevo lowers dyskinesia threshold---my opinion is that it was not surprising as Comtan raises dopamine levels.

Dr
My DH was started on mysolin in June with lottle effrct ( gor Essential Tremots); had been on SInemet since October. On Dec he started on Artane. We still can not say that he has a marked improvement . How does one judge effectiveness? Is his disease progressed & we can't see the improvement, or do you think he still needs adjustments?
How does one know when treatment is optimized? He does not see the neurologist again until March. Should he be seen before then?
The Doctor plans to have him start to come off the Mysoline soon, and we worry that the tremors will be worst?
Thank you SAM55

If the tremor is severe at action (even if there is a rest tremor), it is possible you could still need mysoline or even DBS.

The key to optimal treatment is a slow titration of a cocktail of medications including dopamine agonists, sinemet (probably try up to 3 pills per dose and multiple doses a day), and anticholinergics (artane). We say that patients and docs should go to maximally tolerated doses of these before considering DBS. If there is also an intentional tremor sometimes we later (after we try above) titrate up propranolol and mysoline. Some people will also try clozapine (needs weekly blood monitoring). It may also be necessary to check a gastric emptying study if you see no effects of medications (you may not be absorbing). DBS is a powerful treatment for the cases where tremor is medication resistant.